DESCRIPTION (from applicant's abstract): The research focus of the Effros laboratory is the decline in T cell immune function in the elderly. A major clinical outcome of this diminished immunity is the dramatic increase in infections. This proposal addresses a novel facet of T cell biology that constitutes a fundamental problem for viral immunity, namely, the finite proliferative capacity of human T lymphocytes. Long-term memory to viruses that establish latency and to repeatedly encountered viruses such as influenza may be severely impaired by "replicative senescence," a genetically programmed process affecting all human somatic cells. The notion that the process of replicative senescence impacts viral immunity represents a highly innovative hypothesis that has never been explored, yet may be critical to sustained immunity to both actual infection and repeated vaccination. The proposed studies constitute the first systematic analysis of replicative senescence of virus-specific CD8+ T cells. The specific aims of our research are: I. To document and characterize the process of replicative senescence in virus-specific memory CD8+ T cells; II. To test the hypothesis that the replicative limit of virus-specific CD8+ T cells is due to the progressive decline of telomerase inducibility in these cells. The gene for the telomerase catalytic component (hTERT), previously shown to prevent telomere shortening and replicative senescence in fibroblasts, will be transduced into virus-specific CD8+ T cells; III. To compare the functional properties of virus-specific CD8+ T cells that have enforced hTERT expression with those that have enforced expression of both hTERT and CD28, since in T cells, senescence is associated with loss of CD28 gene expression.